This is an application for competitive renewal of a grant to study neutralization resistance of HIV-1. Responses to vaccines capable of broadly cross-reactive, primary virus neutralization may be effective for prevention of HIV-1 infection. The proposal is based on findings during the previous funding period which demonstrated: 1. Structure-function relationships between the leucine zipper of gp41 and the receptor and coreceptor binding domains of gp120 which modulate both neutralization resistance and high infectivity phonotypes; 2. Primary virus cross-reactivity neutralizing antibody responses occur commonly during chronic HIV-1 infection, in response to epitopes which are conserved within and among virus populations in individual patients; and, 3. The cross-clade, primary virus neutralizing antibodies in HIV-1 Neutralizing Serum (2) are associated with neutralizing antibodies against a unique, conformation-dependent epitope in the V3 region of the envelope protein of the patients virus. The proposal consists of three aims which are intended to: 1. Further elucidate structure-function relationships which modulate the neutralization resistance and high infectivity phenotypes; 2. Evaluate the pathological significance and possible additional mechanisms for these naturally occurring phenotypes; and 3. Define the components and evolution of the primary virus cross-reactive neutralizing antibody response in patients with chronic HIV-1 infection. These studies should elucidate the naturally occurring mechanisms for neutralization resistance of HIV-1, and the nature of antibody responses which can potentially mediate broadly effective protection against these viruses.